Anthelmintic compositions containing benzimidazole derivatives



United States Patent Claims. (Cl. 167-53) This invention relates to compounds useful against helminthiasis. More particularly, it relates generally to new benzimidazoles and to benzimidazole compositions. Still more particularly, it is concerned with 2-(2-naphthyl)-benzirnidazoles and with derivatives thereof. It is concerned further with methods of making such compounds and using them in the treatment of helminthiasis.

This application is a division of our application Ser. No. 112,545, filed May 25, 1961, which application has issued to patent, U.S.- 3,192,226 and which, in turn, is a continuation-in-part of our application Serial No. 22,100, filed Apr. 14, 1960, and now abandoned.

The infection known as helminthiasis involves infestation of the animal body, and particularly the gastrointestinal tract, with various species of parasitic worms. It is a very widespread and serious disease, and the methods heretofore available for its treatment and prevention have not been entirely satisfactory. It is a purpose of this invention to provide a group of benzimidazoles'which are effective in controlling helminthiasis, and Which lack many of the objectionable features of the known anthelmintics.

According to this invention, it has been found that 2-(2'-naphthyl)-benzimidazoles possess a significant degree of anthelmintic activity and may be effectively employed in the treatment and/or prevention of helminthiasis. It is one object of the invention to provide such compounds. It is an additional object to provide compositions containing such substances as an active anthelmintic ingredient. Further objects are the provision of methods of synthesizing such compounds and of using them, and compositions containing them, in controlling helminths. Still other objects will become apparent from the following discussion of the invention.

The compounds useful in treating helminthiasis in accordance with this invention have the general structural formula Rz- N QQ R1 wherein R is hydrogen, a lower alkyl or a lower alkenyl radical, or an acyl group, and R and R represent hydrogen, lower alkyl or lower alkoxy groups. The invention also includes within its scope acid addition salts of these benzimidazoles.

The N-l position of the 2-(2'-naphthyl)-benzimidazoles (R in Formula I) may be substituted with hydrogen, a lower alkyl group such as methyl, ethyl, propyl or isopropyl, or a lower alkenyl radical of the type represented by allyl and methallyl. The alkyl and alkenyl radicals preferably contain less than six carbon atoms. The N-l position may be acylated, preferably with an aralkanoyl, a lower alkanoyl or aroyl radical such as acetyl, propionyl, butyryl, benzoyl and the like. If desired, the siX-membered ring of the benzimidazole nucleus may also be substituted, as with a lower alkyl or lower alkoxy group at the 5- or 6-position. Methyl groups are the preferred lower alkyl substituents although ethyl, propyl and similar lower alkyl radicals may, of course, be employed. Fluorinated alkyl groups, such as a trifluoromethyl substituent, may also be present at the 5 or 6-position of the benzimidazole ring nucleus. The 5- or 6-alkoXy group which may be present is preferably a lower alkoxy radical such as methoxy, ethoxy, isopropoxy and the like. It will be appreciated that when R in these compounds is hydrogen, the 5- and 6-posit'ions of the nucleus are equivalent, and substitution at those positions is often described as 5(6)- substitution. This equivalence or symmetry is, of course, lost when R is other than hydrogen.

Typical examples of compounds which are within the purview of this invention and which :may be prepared as described below are 2-(2'-naphthyl)-benzimidazole, lmethyl-2-(2'-naphthyl) benzimidazole, 1-propyl-2-(2'- naphthyl) -benzimidazole, 1-allyl-2- 2'-naphthyl -benzimidazole, 1-acetyl-2-(2'-naphthyl) benzimidazole, l-propionyl-2-(2'-naphthyl) benzimidazole, l-butyryl-2-(2'- naphthyl) -benzimidazole, 5 (6 -methoXy-2-(2'-naphthyl) benzimidazole, 5 6 -methyl-2- (2'-naphthyl) -menzimidazole, 1,5-diethyl-2-(2'-naphthyl) benzimidazoleJ-benzoyl-2-(2'-naphthyl)-benzimidazole, and the like.

The new 2-(2'-naphthyl)-benzimidazoles are isolated as the free bases by the synthetic processes normally employed, and may be converted to acid addition salts by treatment or intimate contact with an appropriate acid. Typical salts which may be formed in this manner are mineral acid salts such as the hydrohalides, e.g. hydrochloride, hydrobromide, hydroiodide, sulfates, nitrates, phosphates, and the like, aliphatic acid salts such as the acetate, trimethylacetate, t-butylacetate, or propionate, salts of polycarboxylic acids such as the citrate, oxalate, succinate and the like and salts of other insoluble organic acids such as the embonate and hydroxynaphthoate salts. Certain of these salts are much more water soluble than the free bases. This is true of the hydrohalides. Since the solubility may also be decreased by formation of an appropriate salt, it will be seen that the solubility properties of a particular compound may be generally adjusted by judicious selection of a salt. When the acid addition salts are used to treat helminthiasis, it is, of course, desirable that the particular acid employed be an edible. non-toxic one.

The 2-(2-naphthyl)-benzimidazoles are synthesized by a method which comprises broadly the reaction of Z-naphthoic acid or a derivative thereof, such as an ester, amide, nitrile, acid halide or aldehyde, with a compound of the general formula II wherein Y is NO NH or -NHR, R is lower alkyl or lower alkenyl, and R and R are hydrogen, lower alkyl or lower alkoxy. At least one of the R and R substituents is hydrogen.

According to one process, the 2-(2-naphthyl)-benzimidazoles are prepared by intimately contacting o-phenylenediamine and 2-naphthoic acid (or a derivative thereof) in polyphosphoric acid. When 2-naphthoic acid itself is not employed, it is preferred to use the amide or a lower alkyl ester derivative thereof. The process is carried out at elevated temperatures, and preferably at temperatures of about -300 C. The optimum reaction time and temperature will depend to some extent on the particular reactants being employed, but in general good yields are obtained by conducting the process at tempera- 3 tures of about 175 to about 275 C. for from 2 to 6 hours. It may be helpful in some cases to preheat the reaction mixture at about 100-150 C. for a short period of time, and then to complete the process at the higher temperatures referred to above. It is preferred to employ substantially equimolar amounts of the Z-naphthoie acid compound and the diamine, and from about -20 parts by weight of polyphosphoric acid per part of naphthoic acid, although it will be appreciated by those skilled in this art that the relative amount of reactants is not a critical feature of the invention. The desired 2-(2'-naphthyl)-benzimidazoles are recovered by cooling the reaction mixture and diluting with water. Where the benzimidazoles do not crystallize readily under these conditions, they are precipitated by neutralizing the quenched mixture with a base such as ammonium hydroxide, an alkali metal hydroxide or an alkali metal carbonate.

Alternatively, the 2-(2'-naphthyl)-benzimidazole may be synthesized by reacting together o-phenylenediamine and 2-naphthaldehyde in a reaction medium comprising nitrobenzene. Good results are obtained by heating the reaction mixture slowly to the reflux temperature (ca. 210 C.), and maintaining that temperature for a short time. If desired, a solvent such as a lower alkanol may be used to promote the solubility of the reactants at lower temperatures. Such solvents are allowed to distill oir during the heating period. The 2-(2'-naphthyl)-benzimidazoles are readily recovered. In many cases they crystallize directly on cooling the nitrobenzene solution. Alternatively, they may be crystallized by addition of ether or petroleum ether to the nitrobenzene solution. This process is particularly useful for the direct preparation of l-loweralkyl-2-(2-naphthyl)-benzimidazoles from an N-lower alkyl-o-phenylenediamine and 2-naphthaldehyde.

According to a further embodiment of the invention, the benzimidazoles described herein are prepared by condensing Z-naphthaldehyde with a compound of Formula II above. The reaction is preferably brought about by contacting the reactants in a suitable solvent such as a lower alkanol, e.g. methanol, ethanol, isopropanol or tbutanol. The first product formed is the Schitf base of the aldehyde and the primary amine. In normal practice this is not isolated but rather converted directly to the benzimidazole. When an o-phenylenediamine or an N-substituted-o-phenylenediamine is used, the ring closure of the Schiff base to the desired benzimidazole is effected with a suitable oxidizing agent such as cupric acetate, lead tetraacetate, mercuric acetate, air and the like.

Alternatively, in those cases where an o-nitroaniline is one of the starting materials, an ester or an acid halide derivative of Z-naphthoic acid is employed as the other reactant. An intermediate anilide is formed initially. The nitro group is then reduced and benzimidazole formation elfected by treatment of the intermediate anilide with a metal-acid reducing system such as zinc-hydrochloric acid, Zing-acetic acid, iron-hydrohalic acid or tin-hydrohalic aci Where a heavy metal reagent is used to bring about benzimidazole formation in either of the two last-mentioned syntheses, an insoluble heavy metal salt of the 2- (2-naphthyl)-benzimidazole may be produced. This is readily converted to the free benzimidazole by removal of the heavy metal with reagents suitable for this purpose, such as hydrogen sulfide, ammonium polysulfide, ammo nium hydroxide and the like.

In an additional embodiment of the invention, the benzimidazoles are prepared by heating a mixture of an ophenylenediamine or an N-alkyl-o-phenylenediamine and a lower alkyl 2-naphthoate with an aqueous mineral acid such as aqueous sulfuric or phosphoric acid in a closed system, i.e. an autoclave or bomb. The process is conducted at temperatures of from about 120-180 C. for 310 hours, and the benzimidazole recovered from the acid reaction mixture by application of the isolation and purification techniques described above.

1-substituted-2-(2-naphthyl)-benzimidazoles, where R, in Formula I above is alkyl or alkenyl, may further be synthesized by alkylation or alkenylation of the 2-(2'- naphthyl)-benzimidazole itself. According to this method, an alkali metal salt of the benzimidazole, such as the sodium or potassium salt, is treated or contacted with an ester of a strong acid and a lower alkanol or lower alkenol, such as methyl bromide, methyl iodide, allyl bromide and the like, or with an alkyl sulfate such as dimethyl sulfate.

The 1-acyl-2-(2-naphthyl)-benzimidazoles described herein are prepared by acylation of an alkali metal salt of a 2-(2'-naphthyl)-benzimidazole as illustrated by the flow diagram:

where R and R have the same meaning as above, R is a hydrocarboinyl radical, M is an alkali metal and X is a halogen such as chlorine or bromine.

The process is carried out by first converting the 2-(2- naphthyl)-benzimidazole to an alkali metal salt. It is preferred to form the sodium salt by reacting or intimately contacting the benzimidazole with sodium hydride in a suitable solvent medium. Satisfactory results are obtained when a slight molar excess of sodium hydride is employed, although equimolar quantities of benzimidazole and sodium hydride may be used if desired. The reaction is conveniently brought about by warming the reactants at slightly elevated temperatures, but this is not essential and room temperature is satisfactory.

The novel l-acyl-2-(2'-naphthyl)-benzimidazoles are obtained by intimately contacting the benzimidazole alkali metal salt with an acyl halide, and preferably one having less than nine carbon atoms, such as acetyl chloride, acetyl bromide, propionyl chloride, butyryl chloride, valeroyl bromide, benzoyl chloride, phenylacetyl chloride and the like. Normally, the acyl halide is added directly to a solution or suspension of the benzimidazole salt in an inert solvent, and the acylation reaction allowed to proceed at temperatures of room temperature up to about C. Reaction temperatures in the range of 50-75 C. are preferred. The solvent employed as the reaction medium is preferably a hydrocarbon solvent such as benzene, toluene, xylene, petroleum ether and the like either alone or mixed with other solvents miscible therewith, such as dimethylformamide.

The 1-acyl-2-(2-naphthyl)-benzimidazoles thus formed are recovered from the reaction mixture by techniques such as removal of the organic solvent and crystallization of the residual solid from solvents such as ether or mixtures of ether with other solvents.

The 2-(2'-naphthyl)-benzimidazoles described above are active against blood sucking nematodes such as those commonly referred to as whipworms and hookworms and for this purpose are administered to the worm-infested animal, such as sheep, cattle or dogs, orally in admixture with a suitable carrier vehicle. For treating these and similar nematodes, they are administered at daily dose levels in the range of about -600 mg. per kilogram of animal body weight, the preferred level depending on the particular 2-(2'-naphthyl)-benzimidazole being used, the

species of animal being treated, and the type and severity of infection. The compounds may be administered in a single dose or divided into a plurality of smaller doses. Highly satisfactory result are achieved by administering the compounds for only a single day at the desired dose levels. If desired, however, the course of treatment may be extended over a period of days in which case the optimum daily dose level is reduced. Thus, when a group of dogs was fed a single oral dose of 150 mg. of 2(2'- naphthyl)-benzimidazole per kilogram of body weight, the animals expelled hookworms and whipworms, and the fecal egg count was significantly reduced. Similar results were obtained when worm-infested dogs were fed 2-(2'- naphthyl)-benzimidazole in four equal doses of 50 mg. per kilogram of body weight over a two-day period.

The 2-(2-naphthyl)-benzimidazoles described herein are highly effective in controlling the development of worms in that they prevent the larvae from hatching. This is a preferred and highly important use of the compounds.

This property of preventing larval development was demonstrated by feeding 2-(2'-naphthyl)-benzimidazole orallyto mice infected with Nematospiroides dubius and measuringlarval development. The compound was effective in preventing such development when administered at levels of 500, 250, 125 and 62.5 mg. per kilogram of body weight, and moderately active at a 31.25 mg. per kilogram of body weight dose level.

The methods for employing our 2-(2'-naphthyl)-benzimidazolesin treating helminthiasis are not critical and any of the methods now used or available for treating animals infected with or susceptible to parasitic infectionsare satisfactory. In accordance with one aspect of the invention, there are provided anthelmintic compositions wherein the 2-(2-naphthyl)-benzimidazole is dispersed in a suitable carrier vehicle. When these substances are employed therapeutically to treat an established infection, they are conveniently administered in a unit dosage form such as in a capsule, bolus, tablet or as a liquid drench. It will be noted that all of these methods contemplate oral administration since this is the most effective route.

When the 2-(2'-naphthyl)-benzimidazoles are to be administered in dry, solid unit dosage form, capsules, boluses or tablets containing the desired amount of anthelmintic distributed in a pharmaceutically acceptable vehicle or a vehicle acceptable for veterinary use are usually employed. These are prepared by intimately and uniformly mixing the active ingredient with suitable finely divided diluents, fillers, disintegrating agents and/ or binders such as starch, lactose, talc, magnesium stearate, dicalcium phosphate, vegetable gums and the like. These unit dosage formulations may be widely varied with respect to their total weight and content of anthelmintic agent, depending on factors such as the type of host animal to be treated, the dose level desired, and the severity and type of parasitic infestation. For large animals such as sheep, swine or cattle, boluses weighing up to 15 grams may be used although it is preferred to employ boluses weighing from 5-10 grams and containing from 28 grams of the benzimidazole. These boluses as well as smaller size tablets contain binders and lubricants, and are compounded by techniques known in this art. Capsules are readily prepared by mixing the active ingredient with a diluent such as starch or lactose and filling into the capsule. In general, tablets, boluses and drenches containing from about 570% by weight of active ingredient are used to supply the desired dosage of anthelmintic.

In order to treat infected animals by means of a drench, the 2-(2-naphthyl)-benzimidazoles may be mixed with a suspending agent such as bentonite and the solid mixture added to water just prior to administration. Alternatively, ready-to-use drench formulations, such as those disclosed in U.S. Patent No. 2,918,403, may be utilized. The preferred drenches in accordance with this invention contain from about 550% by weightof anthelmintic.

In addition, the benzimidazoles described herein may be administered as a component of the feed of the animals or dissolved or suspended in the drinking water. According to the invention, novel feed compositions are proided in which compounds of Formula I above are present as an active anthelmintic ingredient. Such compositions comprise the benzimidazoles intimately dispersed in or admixed with an inert carrier or diluent. By an inert carrier is meant one that is nonreactive with respect to the 2-(2-naphthyl)-benzimidazole and that may be administered with safety to the animals. The carrier or diluent is preferably one that is or may be an ingredient of the animal ration.

These compositions include feed supplements in which the active ingredient is present in relatively large amounts and which are suitable for addition to the feed either directly or after an intermediate dilution or blending step. Examples of carriers or diluents suitable for such compositions are solid orally ingestible carriers such as distillers dried grains, corn meal, citrus meal, fermentation residues, ground oyster shells, Attapulgus clay, wheat shorts,

molasses solubles, corn cob meal, edible vegetable substances, toasted dehulled soya flour, soybean mill feed, antibiotic mycelia, soya grits, crushed limestone and the like. The anthelmintic agents are intimately dispersed or admixed throughout the solid inert carrier by methods such as grinding, stirring, milling or tumbling. By selecting proper diluents and may by altering the ratio of carrier to active ingredient, compositions of any desired concentration may be prepared. Formulations containing from about 5% to about 50% by weight, and preferably from about 1030% by weight, of active ingredient are particularly suitable for addition to feeds. The active compound is normally dispersed or mixed uniformly in the diluent but in some instances may be sorbed on the carrier.

Examples of typical feed supplements containing a 2-(2'-naphthyl)-benzimidazole dispersed in a solid carrier are:

Lbs. 2-(2-naphthyl)-benzimidazole 20.0 Corn distillers dried grains 80.0'

2-(2'-naphthyl) benzimidazole hydrochloride 5.0 Wheat standard middling 95.0

1-acetyl-2- 2'-naphthyl -benzimidazole 25.0 Soybean mill feed 75.0

l-methyl-2-(2'-naphthyl)-benzimidazole 30.0 Wheat shorts 70.0

2- 2-naphthyl) -5 (6 -methyl-benzimidazole 25 .0 Corn distillers dried grains 75.0

These and similar feed supplements are prepared by uniformly mixing the active ingredient with the carrier or carriers.

These supplements are added to the finished animal feed in an amount adequate to give the final concentration desired for controlling or treating halminthiasis by way of the animal ration. Although the preferred level in feeds will depend on the particular compound being employed and the species of animals to be treated, the 2-(2'-naphthyl)-benzimidazoles of this invention are normally fed at levels of 0.52.0% in the feed. One advantageous method of administering the compounds of this invention to animals whose feeds are conveniently pelleted, such as sheep, is to incorporate them directly in the pellets. For instance, 2-(2-naphthyl)-benzimidazole is readily incorporated in nutritionally adequate alfalfa pellets (during the pelleting operation) at levels of 1-5' grams per pound of pellets for therapeutic use, and at lower levels for prophylactic use, and such pellets fed to the worminfested animals. Alternatively, it may be incorporated in salt licks or salt blocks at any desired concentration (concentrations of 25% by weight are conveniently employed) whereby large animals such as sheep, cattle and swine would be enabled to receive the anthelmintics with their salt.

Alternatively, the compounds of Formula I above may be administered to domesticated animals such as sheep and cattle by admixing them with the protein-vitamin supplements employed as top dressings in the feed of such animals. When this route of administration is to be used, good results are obtained by adding from 5-15 grams of anthelmintic to a pound of protein supplement.

The following examples are given for the purpose of illustration and not by way of limitation:

EXAMPLE 1 8 g. of o-phenylenediamine is suspended with stirring in 250 ml. of ethyl alcohol. g. of Z-naphthaldehyde is added portionwise with stirring to this suspension, and the mixture is stirred for 5 hours at room temperature. A solution of 13 g. of copper acetate [Cu(OAc) in 200 ml. of water is then added dropwise with vigorous stir ring. After standing at room temperature for 5 hours the solid copper salt of 2-(2'-naphthyl)-benzimidazole is fil tered off, Washed with water and with 100 ml. of 1:1 ethanol-water. The green salt is then suspended with stirring in 40.0 ml. of 1:1 ethanol-water and a stream of hydrogen sulfide passed into the suspension to saturation. After about 45 minutes the precipitated copper sulfide is filtered and washed with boiling ethanol to remove any occluded 2-(2-naphthyl)-benzirnidazole. The filtrate and washings are combined and concentrated to dryness in vacuo. 13. 5 got crude 2-(2'-naphthyl)-benzimidazole are obtained. The solid is dissolved in the minimal amount of warm ethanol-water and the solution treated with a small amount of decolorizing charcoal. The charcoal is filtered off and the 2-(2-naphthyl)-benzimidazle crystallized by chilling the solution. 9 g. are obtained, M.P. 210-216 C. On recrystallization from ethyl acetate, the product melts at 215-216 C.

EXAMPLE 2 17.2 g. of ethyl 2-naphthoate and 11.5 g. of o-phenylenediamine are mixed and added slowly to 270 g. of polyphosphoric acid. The mixture is heated slowly with stirring to 245 C. and maintained at this temperature for 2% hours. The hot solution is then poured onto about 200 g. of ice and the mixture stirred. It is filtered and the filtrate neutralized slowly with 30% sodium hydroxide until the 2-(2'-naphthyl)-benzimidazole precipitates. It is filtered, washed with water, and dried in air. This product is extracted with hot ethanol, benzene is added to the extract and the solution boiled to remove traces of water. On concentration of the solution to a small volume and cooling, substantially pure 2-(2'-naphthyl)-benzimidazole crystallizes.

3 g. of this material is added slowly with stirring to 150 ml. of ethanolic hydrogen chloride. The solution is treated hot with 2 g. of activated charcoal, the charcoal removed by filtration and the solution cooled. Three volumes of ethyl ether are added and the mixture chilled, whereupon 2-(2'-naphthyl)-benzimidazole hydrochloride crystallizes. It is recovered by filtration, washed with ether and air dried.

EXAMPLE 3 (A) 9 g. of 2-naphthaldehyde in 12 ml. of ethanol is added with stirring to a suspension of 11 g. of o-phenylenediamine in 40 ml. of nitrobenzene. The mixture is stirred at room temperature for 15 minutes and then heated slowly to 210 C. During the heating period, the ethanol is removed by distillation. As soon as the temperature of the reaction mixture reaches 210 C., it is cooled with stirring to about 10 C. 2-(2'-naphthyl)- benzirnidazole crystallizes, is recovered by filtration and washed with ether. If desired, the product may be purified by recrystallization from ethanol.

(B) 1.8 g. of 2-(2'-naphthyl)-benzimidazole in a mixture of 40 ml. of benzene and 17 ml. of dimethylformamide is treated at 60 C. with 0.4 g. of sodium hydride. The sodium hydride is added as a 50% emulsion in oil mixed with 2 m1. of benzene. The addition is carried out slowly and the mixture heated with stirring at 60 C. for 45 minutes after completion of the sodium hydride addition. At the end of this time, 1.5 g. of benzoyl chloride is added slowly at a temperature of 50 C. and the mixture heated for 35 minutes at that temperature with stirring. It is then cooled to about 10 C., 2.0 ml. of water added and the entire mixture washed with 5% sodium bicarbonate solution. The organic solvent solution is filtered to remove any solid material and the benzene solution concentrated to dryness in vacuo. The residue is crystallized from ethyl ether to give l-benzoyl-2-(2'-naphthyl -benzimidazole.

When an equivalent molar amount of acetyl chloride is employed instead of benzoyl chloride in the above procedure, there is obtained 1-acetyl-2-(2'-naphthyl)-benzimidazole.

EXAMPLE 4 (A) 7 g. of 2-naphthoyl acid chloride and 7 g. of o-nitroaniline are stirred together in 20 ml. of pyridine at room temperature for about 10 hours. The mixture is then poured into ice water and the solid nitroanilide recovered by filtration. It is washed with dilute aqueous sodium carbonate solution, and added to 70 ml. of glacial acetic acid. 40 ml. of 6 N-hydrochloric acid is added slowly to the acetic acid mixture followed by 30 g. of zinc dust. The zinc is added slowly in small portions. After the zinc addition is completed, and the reaction is essentially finished (by visual observation), the mixture is filtered and the filtrate neutralized with concentrated ammonium hydroxide. 2-(2-naphthyl)-benzimidazole precipitates on neutralization. It is isolated by filtration, washed with ice water, and purified by recrystallization from ethyl acetate.

(B) To 2.4 g. of 2-(2-naphthyl)-benzimidazole in 20 ml. of dry dimethylformamide is added 0.5 g. of a 52% sodium hydride emulsion in mineral oil. The mixture is stirred at room temperature for about 20 minutes and then heated to 50 C. for 5 minutes. It is cooled to room temperature and 1.5 g. of methyl iodide in 2 ml. of dimethylformamide added slowly to the cooled solution containing the sodium salt of 2-(2-naphthyl)-benzimidazole. The reaction mixture is heated to about C., for 20 minutes, cooled to room temperature, and 20 ml.

of water added thereto. The mixture is extracted With" three 1 0-ml. portions of ethyl ether, the ether extracts combined, washed with water, dried over sodium sulfate, filtered and the ether removed in vacuo. The residual solid is l-methyl-2-(2'-naphthyl)-benzimidazole, which is purified by crystallization from ethyl acetate.

When the above process is carried out employing allyl bromide in place of methyl bromide, 1-allyl-2-(2'-naphthyl)-benzimidazole is produced.

EXAMPLE 5 To a solution of 13.8 g. of 4-methoxy-1,2-diaminobenzene in ml. of ethanol is added 15.6 g. of 2-naphthaldehyde. The reaction mixture is stirred at room temperature for 2 hours, during which time the Schiif base forms from the aldehyde and primary amine.

20 g. of cupric acetate monohydrate in ml. of water is added in small portions to the solution of Schilf base. The resulting mixture is refluxed gently with stirring until precipitation of the copper salt of 2-(2'-naphthyl)- 5 (6)-methoxy benzimidazole is complete. The mixture is then cooled, filtered and the solid washed with water. The solid copper salt is suspended in about 240 ml. of ethanol and the mixture saturated with hydrogen sulfide. The

precipitated copper sulfide is removed by filtration and the filtrate concentrated to dryness in 'vacuo. The resulting 'residual solid is substantially pure 2-(2'-naphthyl)- (6)-methoxy benzimidazole.

The hydrochloride salt is obtained by dissolving the product in hot alcoholic hydrogen chloride, treating the hot solution with activated charcoal, removing the charcoalby filtration, and adding about 3 volumes of ether to the alcoholic solution. The acid salt crystallizes on cooling. 1

EXAMPLE 6 13.0 g. of 4-methyl-l,Z-diaminobenzene and 19 g. of methyl Z-naphthoate are added to 325 g. of polyphosphoric acid which has been preheated to about 80 C. in a nitrogen atmosphere. The mixture is stirred for 50 minutes at 125 C., and the temperature then raised to 220 C. for 90 minutes. The solution is cooled to about 100 C. and poured slowly with stirring into 400 ml. of ice water. An amorphous solid is filtered off and the filtrate neutralized to a pH of about 7 with 30% sodium hydroxide solution. The crystalline solid which precipitates is filtered, washed with water and dried. This solid is extractedwith 3X 100-ml. portions of acetone. The com-' bined acetone extracts are treated with decolorizing charcoal. The charcoal is filtered off and the filtrate concentrated to dryness to give substantially pure 5-m-ethyl-2- (2'-naphthyl)benzimidazole.

EXAMPLE 7 A bolus of 2-(2'-naphthyl)benzimidazole and having the compositon Gm. 2-(2'-naphthyl)-benzimidazole 2.0 Dicalcium phosphate 3.0 Starch 0.535 Guar gum (through 60-mesh screen) 0.15 Talc (through 60-mesh screen) 0.14 Mg stearate (through 60-mesh screen) 0.04

is prepared in the following manner:

The dicalcium phosphate is thoroughly mixed with the 2-(2'-naphthyl)benzimidazole and the mixture reduced to a particle size finer than 60 mesh. To the mixture is added 0.330 gm. of starch in the form of an aqueous starch paste and the resulting mixture is granulated in the usual manner. The granules are then passed through a #10 mesh screen and dried at 110130 F. for about 8 hours. The dried material is then passed through a #16 mesh screen. The guar gum and the balance of the starch are added andthe mixture thoroughly blended. The remainder of the ingredients are then added and the whole thoroughly mixed and compressed.

A bolus providing 4.0 gm. of 1-benzoyl-2(2'-naphthyl)- benzimidazole is prepared as above using twice the amount of ingredients.

is prepared in the following manner:

The dicalcium phosphate is thoroughly mixed with the 1-rnethyl-2-(2-naphthy1)benzimidazole and the mixture reduced to a particle size finer than 60 mesh. To the mixture is added 0.430 gm. of starch in the form of an aqueous starch paste and the resulting mixture is granulated in the usual manner. The granules are then passed through 10 a-#10 mesh screen and dried at 110-130' F. for about 8 hours. The dried material is then passed through a #16 mesh screen. The guar gum and the balance of the starch are added and the mixture thoroughly blended. The remainder of the ingredients are then added and the whole thoroughly mixed and compressed.

EXAMPLE 9 Drenches having-the following composition are prepared by standard formulating methods:

Drenches may also be prepared in bulk for subdivision prior to use. The following vehicles are suitable:

Benzalkonium chloride (12.8% soln.) ml 40 Antifoam AF emulsion gm 4 Hydroxyethyl cellulose gm 20 Distilled water to 2000 ml.

Benzalkonium chloride (12.8% soln.) ml 0.5 Antifoam AF emulsion gm 4 Hydroxyethyl cellulose gm 20 Distilled water to 2000 ml.

The compounds of Formula I above are added to the vehicles in concentrations in the range of 6-25 gm./ ml.

The benzalkonium chloride used in the drench vehicles isda mixture of C C dimethylbenzylammonium chlor1 es.

Any departure from the above description which conforms to the present invention is intended to be included Within the scope of the claims.

What is claimed is:

1. An anthelmintic composition which comprises an animal feedhaving dispersed therein a compound selected from the class consisting of a benzimidazole of the formula and non-toxic acid addition salts thereof, where R and R are selected from the class consisting of hydrogen, loweralkyl, and loweralkoxy groups, at least one of R and R being hydrogen.

2. The composition-of claim 1 wherein the benzimidazole is 2-(2-naphthyl)benzimidazole.

3. The composition of claim 2, which composition con tains from 0.5-2% by weight of said benzimidazole.

4. An anthelminitic composition which comprises a bolus containing from 5-70% by Weight of a compound selected from the class consisting of a benzimidazole of being hydrogen and the balance being a pharmaceutically the formulaacceptable vehic1e.

5. The composition of claim 4 wherein the henzimida- I I zole is 2-(2-naphthyl)-benzimidazole.v R2 --N 5 J References Cited O fi Abramovitch, Chem. Am, vol. 51, 1957, page 13840.

H I Efros et al., Chem. Abst., vol. 42, 1948, page 5903. 1 Rao et al., Chem. Abst., vol. 51, 1957, page 1149.

10 Rao et al., Chem. Abst., vol. 52, 1958, page 1146.

and non-toxic acid addition salts thereof, where R and R 5 AM ROSEN, Primary Examineh are selected from the class consisting of hydrogen, oweralkyl, and loweralkoxy groups, at least one of R and R ALBERT MYERS, Exammer- 

1. AN ANTHELMINTIC COMPOSITION WHICH COMPRISES AN ANIMAL FEED HAVING DISPERSED THEREIN A COMPOUND SELECTED FROM THE CLASS CONSISTING OF A BENZIMIDAZOE OF THE FORMULA 